Tuberculosis in HIV-infected individuals is apt to progress rapidly, resulting in very high mortality rates, especially in cases of MDR-TB. It has become critical in this era of growing rates of dual HIV + M. tuberculosis infections to develop treatment regimens suitable for short- course therapy, including new antituberculosis agents highly effective against both susceptible and drug-resistant M. tuberculosis. The main goal of this project is to develop ultrashort (3-4 months) treatment regimens incorporating powerful new antituberculosis drugs with long-lasting effects that may make these regimens feasible for intermittent administration. Some new regimens will be directed against isoniazid-resistant and MDR strains. Prevention of relapses will be addressed by evaluation of agents active against dormant bacilli. Human macrophage model in a number of modifications will be used to evaluate the merits of various regimens. These will be supplemented with experiments in culture media, especially drug-combination experiments, and in our newly developed models for dormant and semi-dormant cultures. The interactions between the drugs and bacterial residing in macrophages will be studied to define the intracellular drug traffic in infected and non-infected cells using autoradiography technique at the electron microscopic level. The key elements in new ultra-short regimens are the long-lasting rifamycins (rifapentine and KRM-1648) that can be highly effective when given only once or twice a week. New regimens will be developed against isoniazid- monoresistant strains, by replacing isoniazid with new isoniazid derivatives that do not show cross-resistance with isoniazid. Regimens to be studied against M. tuberculosis strains resistant to isoniazid, rifampin and pyrazinamide or isoniazid, rifampin and streptomycin (MDR) will include powerful substitutes, particularly isoniazid derivatives, pyrazinamide derivatives, aminosidine, and novel cell-wall synthesis inhibitors. These agents will be developed either under Projects No. 4 and No. 5, and Core A, or by collaboration with Bristol-Myers Squibb which is committed under Project No. 1 to perform targeted selection of mycolic acid synthesis inhibitors. Cross-resistance with the conventional drugs will be studied under Project No. 1. Preventive therapy against isoniazid-resistant and MDR strains will be evaluated using levofloxacin, rifapentine, pyrazinamide, newer agents, and their combinations. Some of the regimens will include metronidazole, peptide antibiotics, and probably other newly synthesized agents active against dormant subpopulations of m. tuberculosis persisting in anaerobic conditions. The most promising regimens will then be evaluated under Project No. 2 in a murine model.